Dyphylline, 7-(2,3-dihydroxypropyl)-3,7-dihydro-1,3-dimethyl-1H-purine-2,6-dione or 7-(2,3-dihydroxypropyl)-theophylline, is described in U.S. Pat. No. 2,575,344. It is a smooth muscle relaxant. The Physician's Desk Reference (PDR), 34th edition, p. 638, lists several pharmaceutical preparations thereof which are said to exert the general pharmacologic actions of theophylline and of aminophyllin, i.e. bronchodilating, myocardial stimulating, diuretic, and coronary, pulmonary, and renal vessels vasodilating actions, of which the bronchodilator activity is the most important in human therapy. The compound is highly soluble, is readily absorbed and well tolerated upon oral administration as well as uniquely suitable for intramuscular injection. In the latter method of administration dyphylline has been shown to be superior to aminophyllin and to theophylline. Another significant advantage to dyphylline is the fact that it has a low incidence of causing gastric irritation.
Probenecid 4-[(dipropylamino)sulfamyl]benzoic acid or p-(dipropylsulfamoyl)benzoic acid, is described in U.S. Pat. No. 2,608,507. It is an uricosuric agent and a renal tubular blocking agent for antibiotics. In particular, P is known to inhibit the tubular secretion of penicillin and thus to elevate penicillin plasma levels. For the latter reason P is widely used as an adjuvant in penicillin therapy, not only with respect to natural penicillin G but also with respect to a large number of semi-synthetic penicillins, such as ampicillin, methicillin, oxacillin, cloxacillin, or nafcillin. P is also used as an adjuvant in cephalosporin therapy.
The pharmacologic actions of D have been studied by P. V. Maney et al. (J. Amer. Pharm. Assoc., Sci. Ed., 35:266, 1966) and J. D. McColl et al. (J. Pharmacol. Exper. Therap., 116:343, 1956). The bronchodilator activity appears to be the most important, and D is most commonly used for the treatment of bronchial asthma and of reversible bronchospasms associated with chronic bronchitis and emphysema; see previously cited PDR, pp. 638 and 639. The only drawback of D would seem to be its short half-life (cf. B. Isaksson et al., Acta Med. Scand., 171:33, 1962, and F. E. R. Simons et al., J. All. Clin. Immunol., 56:347, 1975), which necessitates frequent administration of repeated doses of the drug (cf. K. J. Simons et al., J. Clin. Pharmacol., 17:237, 1977). Contrary to closely related xanthine derivatives, such as caffeine or theophylline, which are all metabolized, dyphylline is substantially not metabolized and is excreted in the urine in unchanged form (cf. L. G. Giscion et al., Am J. Hosp. Pharm., 36:1179, 1979). It has recently been shown that the plasma half-life of D (following oral administration) is 1.8.+-.0.2 hours, with 83.+-.5 percent of the administered dose being recovered unchanged in the urine within 24 hours (cf. K. J. Simons et al., J. Pharm. Sci., 68:1327, 1979).
The pharmacology of P has been extensively studied, in particular its uricosuric activity [cf. A. B. Gutman et al., Transactions of the Association of American Physicians, 64:279 to 288 (1951); A. B. Gutman, Advances in Pharmacology, 4:91 to 142 (1966); J. H. Talbott et al., "Gout and Uric Acid Metabolism", pp. 225 to 230, Stratton Intercontinental Medical Book Corporation, New York, 1976; V. J. Zarro, "Pharmacology of Gout", in Lowenthal and Major (Ed), "Clinical Therapeutics", pp. 343 to 346, Grune and Stratton, New York, 1978], its effect on penicillin excretion and its effects as an inhibitor of active transport of catecholamines and precursors thereof in the brain.
The "Physicians' Desk Reference" (PDR), 31st Edition, 1977, reflects marketed dosage forms and other products for:
D- PA0 P- PA0 1. D is actively excreted by the renal tubule of the chicken at a rate of one-half that of a compound (tetraethylammonium) completely excreted in one pass through the kidney, and PA0 2. P dose-dependently inhibits this active excretion of D. Infusion of 1.8 .mu.mol/min. inhibits excretion of 100 .mu.g/min. of D by 60 percent. This inhibition increases with increasing infusion rates of P to 83 percent at an infusion rate of 16 .mu.mol/min. of P.
tablets, liquid and long-acting tablets (p. 610) PA1 tablets (p. 744) PA1 tablets, elixir, ampuls (pp. 925 and 926) PA1 injection, tablets, elixir (pp. 1010 and 1011) PA1 capsules, liquid (p. 1381) PA1 tablet, oral liquid (p. 1382) PA1 oral suspension (p. 660) PA1 tablets (pp. 1067 and 1068) PA1 capsules (p. 1539) PA1 tablets (p. 1754) PA1 tablets (p. 1757)
Treatment with and use of D are well established, as are suitable dosages for administration of P.